Project Summary Diabetes is increasing globally and more than 9% of the US population has diabetes, with an additional 86 million pre-diabetic adult Americans. Type 1 diabetes mellitus (T1D) affects nearly 1.5 million Americans, accounting for almost $18 billion annually in healthcare costs. Diabetic-related complications such as retinopathy and cardiovascular disease receive much public attention, and 3 corneal disorders including keratopathy, dry eye, and surface insensitivity lead to vision loss, elevated healthcare costs, and decreased job productivity. This application focuses on the Opioid Growth Factor (OGF) ? Opioid Growth Factor Receptor (OGFr) regulatory system and blockade by naltrexone (NTX) to prevent ocular surface complications arising from Type 1 diabetes (T1D). Preventive intervention of diabetes-related complications remains an unmet medical need. The underlying hypothesis in this proposal is that the OGF-OGFr axis becomes dysregulated during the development of diabetes leading to over-expression of the inhibitory peptide and/or dysregulation of OGFr thus causing diabetes- associated ocular surface complications. The proposed research will i) Determine the temporal course and magnitude of defects in the OGF-OGFr regulatory pathway during the development of T1D in rats in order to properly initiate preventive therapy, 2) Determine whether topical or systemic administration of NTX prevents or delays the appearance of ocular surface complications. 3) Identify other molecular and protein biomarkers related to diabetes such as delayed corneal wound healing, dry eye, and insensitivity, and determine whether NTX intervention alters their expression and function. This knowledge will advance precision medicine approaches for the prevention and treatment of diabetic complications. This application represents the culmination of several decades of research determining that OGF-OGFr blockade with NTX is effective at treating diabetic ocular surface complications, and for the first time, will determine the ability of such blockade by NTX to prevent diabetic ocular surface complications. There is evidence that diabetes is accompanied by dysregulation in expression of endogenous opioids (i.e., OGF) and their receptors leading to an elevated expression of inhibitory growth factors. For more than 2 decades our laboratory has conducted research to determine the role of this regulatory axis in contributing to diabetic complications in diabetic rat, mouse, and rabbit and demonstrated that topical NTX reverses dry eye to normal tear production, accelerates delayed corneal wound healing, and restores the diabetic complication of decreased corneal sensitivity to normal in these diabetic animals. The proposed research will determine for the first time the ability of OGF-OGFr axis blockade by NTX to prevent these complications. Our research team has clinical and basic science expertise in all aspects of this research and will be able to rapidly translate warranted findings to the clinic.